Updated results of a randomized phase II study comparing two schedules of temozolomide in combination with sorafenib in patients with advanced melanoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8527-8527 ◽  
Author(s):  
R. Amaravadi ◽  
L. M. Schuchter ◽  
D. F. McDermott ◽  
A. Kramer ◽  
L. Giles ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Prior History ◽  
Prior Therapy ◽  
Optimal Dosing ◽  
Significant Difference ◽  
Grade 3 ◽  
Induced Apoptosis

8527 Background: The preliminary results for 90 patients (pt) on this 4-arm phase II trial testing sorafenib (SO), an oral Raf kinase/VEGFR2 inhibitor, and temozolomide (TEM) in pt with metastatic melanoma (MM) were presented in 2006. Since then 88% of target accrual is completed and the study is open at a second institution. The primary objective of this study is to estimate the duration of progression- free survival (PFS). Secondary objectives are to determine the optimal dosing of TEM, response, and toxicity rates. Correlative studies include BRAF genotyping and assessment of intratumoral Raf inhibition, and apoptosis. Methods: Pt with MM and ECOG PS<2 are eligible. Prior therapy is allowed. Target accrual is 167 pt in 1 stage. All pt receive SO 400 mg po bid continuously. After 1 week of SO alone, pt without brain metastasis or prior TEM (A+B) are randomized to receive either extended dosing (ED): TEM 75 mg/m2 po qd for 6/8 weeks (Arm A), or standard dosing (STD): TEM 150 mg/m2 po qd for days1–5/28 (Arm B). Pt with prior TEM are treated with ED (Arm C) and pt with brain metastasis without prior TEM are treated with STD (Arm D). Responses are assessed using RECIST. Results: Accrual is complete for arms A and B. Results for 147 pt were evaluated ( Table ). SO + TEM resulted in a 19% overall response rate (ORR) [95% CI 11–30%] for pt on arms A+B. In this group, 3/78 pt (4%) developed CNS metastases while on study. Pt on arm D had a 17 % ORR [95% CI 7–34%]. Common grade 3 toxicities were hand-foot syndrome (14%), rash (9%), nausea (9%), and diarrhea (5%). Grade 3 lymphopenia was more common in arm A v. B (43% v. 16%, p=0.01). No significant difference in PFS was found between pt with WT v. mutant BRAF (n=33). Therapy-induced apoptosis was found in 8/9 serial biopsies. Analysis of MAPK phosphorylation in serial biopsies is planned. Conclusions: Updated results confirm the encouraging antitumor activity and tolerability of SO + TEM in pt with MM without a prior history of TEM. No significant financial relationships to disclose. [Table: see text]

Preliminary results of a randomized phase II study comparing two schedules of temozolomide in combination with sorafenib in patients with advanced melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8009-8009 ◽  
Author(s):  
R. K. Amaravadi ◽  
L. M. Schuchter ◽  
A. Kramer ◽  
S. F. Barth ◽  
J. Villanueva ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Prior Therapy ◽  
Optimal Dosing ◽  
Hand Foot Syndrome ◽  
Correlative Studies ◽  
Grade 3 ◽  
Ecog Ps

8009 Background: Sorafenib (SO) is an oral Raf kinase/VEGFR-2 inhibitor that has anti-melanoma activity when given with carboplatin/paclitaxel. The primary objective of this study is to estimate the duration of progression-free survival (PFS) for patients with metastatic melanoma (MM) taking SO + temozolomide (TEM). Secondary objectives are to determine the optimal dosing of TEM when given with SO, response, and toxicity rates. Correlative studies include BRAF genotyping and assessment of intratumoral Raf inhibition. Methods: Patients with MM and ECOG PS<2 are eligible. Prior therapy is allowed. Accrual is designed for 167 patients in one stage. All patients receive SO 400 mg po bid continuously. After one week of SO alone, patients without brain metastasis and no prior TEM are randomized to receive either extended daily dosing (EDD): TEM 75 mg/m2 po qd for 6 /8 weeks (Arm A), or standard dosing (STD): TEM 150 mg/m2 po qd for days1–5/28 (Arm B). Patients with prior TEM use are treated with EDD (Arm C) and patients with brain metastasis without prior TEM are treated with STD (Arm D). Responses are assessed using RECIST criteria. Results: 65 patients were evaluated for toxicity. Of these, 58 received SO + TEM and were evaluable for response (Table). SO + TEM resulted in a 24% overall response rate (ORR) [95% CI 11–41%] in patients without brain metastasis or prior TEM and 20% ORR [95% CI 3–56%] in patients with brain metastasis and no prior TEM. Observed grade 3 toxicities attributable to study medication were: hand-foot syndrome (12%), rash (8%), nausea (5%), anorexia (8%), and hypertension (3%). Nausea and anorexia were more prevalent with STD. Tumor blocks and 8 paired biopsy samples have been collected for correlative studies. Conclusions: Initial phase II results demonstrate encouraging antitumor activity and safety profile for SO + TEM in MM. Updated PFS data, response and toxicity rates, and correlative results will be presented. [Table: see text] [Table: see text]

scholarly journals Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma

2019 ◽  
Vol 37 (16) ◽  
pp. 1424-1431 ◽  
Author(s):  
Lara E. Davis ◽  
Vanessa Bolejack ◽  
Christopher W. Ryan ◽  
Kristen N. Ganjoo ◽  
Elizabeth T. Loggers ◽  
...  
Keyword(s):  
Phase Ii ◽  
Progression Free Survival ◽  
Double Blind ◽  
Multikinase Inhibitor ◽  
Prior Therapy ◽  
End Point ◽  
Metastatic Osteosarcoma ◽  
Significant Difference ◽  
Grade 3 ◽  
Line Of Therapy

PURPOSE SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort. PATIENTS AND METHODS This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who had received at least one prior line of therapy. Patients were randomly assigned at a ratio of one to one to regorafenib or placebo. Crossover was allowed at time of disease progression. PFS was the primary end point of the study, which was powered to detect a difference of at least 3 months in median PFS. RESULTS Forty-two patients from 12 centers were enrolled between September 2014 and May 2018. Median age was 37 years (range, 18 to 76 years). Patients had received an average of 2.3 prior therapy regimens. Ten patients receiving placebo crossed over to active drug at time of progression. Study enrollment was stopped early, after a data safety monitoring committee review. Median PFS was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0 to 7.6 months) versus 1.7 months (95% CI, 1.2 to 1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.85; P = .017). In the context of the crossover design, there was no statistically significant difference in overall survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation. CONCLUSION The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.

scholarly journals Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study

2020 ◽  
Vol 38 (13) ◽  
pp. 1455-1462 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Galina G. Lagos ◽  
Raymond L. Comenzo ◽  
Jeffrey A. Zonder ◽  
Keren Osman ◽  
...  
Keyword(s):  
Phase Ii ◽  
Light Chain ◽  
Progression Free Survival ◽  
Complete Response ◽  
Multicenter Trial ◽  
Primary Objective ◽  
Al Amyloidosis ◽  
Prior Therapy ◽  
Hematologic Response ◽  
Grade 3

PURPOSE No established treatments exist for relapsed/refractory systemic light-chain (AL) amyloidosis. Bendamustine has shown potential in the treatment of multiple myeloma. We conducted a phase II, multicenter trial to assess the efficacy and safety of bendamustine with dexamethasone (ben-dex) in patients with persistent or progressive AL amyloidosis after ≥ 1 prior therapy. METHODS The trial enrolled 31 patients who received bendamustine on days 1 and 2 (100 mg/m2 intravenously) with 40 mg of weekly dexamethasone in 28-day cycles until disease progression or up to 6 cycles after complete hematologic response. The primary objective was the rate of partial hematologic response (PR) or better. RESULTS Patients received a median of 4 cycles (range, 2-12 cycles) with 57% of patients achieving a PR or better (11% complete response, 18% very good PR). The overall organ response was 29% among the 24 patients who had measurable organ involvement. Treatment was well tolerated with no grade 5 treatment-related adverse events (AEs). Sixty-five percent of patients had a therapy-related grade 3-4 AE. The most common AEs included myelosuppression, fatigue, and nausea/vomiting. The median overall survival was 18.2 months (95% CI, 11.3 to 43.8 months), and hematologic response was associated with prolonged survival ( P = .0291). The median progression-free survival was 11.3 months (95% CI, 5.0 to 15.4 months). CONCLUSION Overall, ben-dex is a viable treatment option with substantial efficacy and limited toxicity for patients with pretreated AL amyloidosis who have limited therapeutic options. This trial was registered at (ClinicalTrials.gov identifier: NCT01222260 ).

A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 307-307 ◽  
Author(s):  
Andrea Borghese Apolo ◽  
Howard L. Parnes ◽  
Ravi Amrit Madan ◽  
James L. Gulley ◽  
John Joseph Wright ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Primary Objective ◽  
Response To Therapy ◽  
Bone Lesions ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Visceral Metastases ◽  
Carcinoma Of The Bladder ◽  
Grade 3

307 Background: Translational studies have shown that shed MET levels in serum and urine of pts with UC correlate with stage and visceral metastases and that cabozantinib reverses HGF-driven UC cell growth and invasion. These data support the evaluation of cabozantinib in pts with mUC. Methods: In this phase II study, pts receive cabozantinib 60 mg daily in 28-day cycles. There are 3 study cohorts (1) mUC, (2) bone only mUC (3) metastatic rare bladder histology. The primary objective is to determine the response rate (RR) by RECIST. Response is assessed every 2 cycles. Tissue, blood, and urine were collected on all pts to test for MET/HGF and immune subsets. Results: 26 out of 55 pts have enrolled (19 M, 7 F): median age 62 (42-82) and median KPS of 80%. Primary sites include bladder (77%) and upper tract UC (23%). Prior therapy includes 30% pts with 1 regimen, 39% with 2, 15% with 3, 8% with 4 and 8% with 6. 81% of pts had visceral metastases (lung, liver and bone) and 19% lymph node only metastases. 23 pts (19 in cohort 1, 3 in cohort 2 and 1 in cohort 3) were evaluable for response after completing at least 4 weeks of therapy. In cohort 1, 2 pts achieved PR (1 remained on study for 10 months and 1 remains on study after >12 months of therapy); 7 pts had SD for at least 16 weeks (1 remained on study for 11 months); 10 had PD; 1 is too early to assess for response; 1 was removed before restaging for toxicity and 1 was removed for not meeting eligibility. The objective RR is 11% and SD 37% for a clinical benefit of 48%. In cohort 2, 1 of 3 pts had a near resolution of bone lesions on NaF PET/CT for 11 months. In cohort 3, only pt enrolled (squamous cell carcinoma of the bladder) achieved SD for 16 weeks. Mixed responses with regression of lung, bone or lymph nodes were observed in 30% of pts with PD. Grade 3/4 toxicities included: fatigue (8%), hyponatremia (8%), hypophosphatemia (8%) diarrhea (4%), thromboembolism (4%), transaminitis (4%), hypothyroidism (4%), thrombocytopenia (4%), dysphonia (4%), hypomagnesemia (4%), creatinine increase (4%) and proteinuria (4%). Conclusions: Cabozantinib has clinical activity in pts with relapsed or refractory mUC with manageable toxicities. Further studies are underway to correlate response to therapy with MET expression. Clinical trial information: NCT01688999.

RECIST and iRECIST criteria for the evaluation of nivolumab + ipilimumab combination in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC): Results of the GERCOR NIPICOL phase II study.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 101-101 ◽  
Author(s):  
Romain Cohen ◽  
Jaafar Bennouna ◽  
Julie Henriques ◽  
Christophe Tournigand ◽  
Christelle De La Fouchardiere ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Low Frequency ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Free Survival ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

101 Background: Immune checkpoint inhibitors (ICKi) are highly effective for MSI/dMMR mCRC pts. RECIST1.1 criteria are reported to underestimate response to ICKi. The GERCOR NIPICOL phase II study aimed to evaluate disease control rate (DCR) using RECIST1.1 and iRECIST for MSI/dMMR mCRC pts treated with nivolumab (NIVO) and ipilimumab (IPI). Methods: MSI/dMMR mCRC pts previously treated with fluoropyrimidines (FP), oxaliplatin (OX) and irinotecan (IRI) ± targeted therapies received NIVO 3 mg/kg + IPI 1 mg/kg Q3W for 4 cycles then NIVO 3 mg/kg Q2W until progression or a maximum of 20 cycles. CT-scan tumor assessments were done every 6 weeks during 24 weeks and then every 12 weeks. Primary objective was DCR at 12 weeks (12wDCR) according to RECIST1.1 and iRECIST by central review. Response rates and progression-free survival (PFS) by central review were secondary objectives. A one-stage Fleming design was used with a targeted improvement of 12wDCR from 70% to 85%. Results: Of 57 pts included between Dec 2017 and Nov 2018, 43.9% had received ≥ 3 prior lines including FP (100%), OX (100%), IRI (95.5%), antiangiogenics (57.9%) and anti-EGFRs (45.6%). 17.5% of pts had BRAF mutation and 27.5% Lynch syndrome. Grade 3-4 treatment-related adverse events were reported in 49.1% of pts, mainly hepatitis (12.3%). 12wDCR was 86.0% and 87.7% using RECIST1.1 and iRECIST respectively, with only 1 pseudo-progression (1.8%) observed during the first 12 weeks, and one later. Kappa coefficient between RECIST and iRECIST 12wDCR was 0.92 (95%CI 0.77-1.0). Best observed responses with RECIST1.1/iRECIST were: 2/2 complete responses (3.5/3.5%), 19/19 partial responses (33.3/33.3%), 30/31 stable diseases (52.6/54.4%) and 3/2 disease progressions (5.3/3.5%), with 3 pts not evaluable (cancer-related deaths before first evaluation). Conclusions: Combination of NIVO and IPI in MSI/dMMR mCRC is associated with a low frequency of pseudo-progression and high DCR rate. PFS will be evaluated in Dec 2019, with all pts having completed the predefined 1-year of ICKi therapy. Clinical trial information: NCT033501260.

Preliminary data from a phase II study of cetuximab with irinotecan in heavily pretreated patients with epidermal growth factor (EGFR)-expressing metastatic colorectal cancer (mCRC): LABEL

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14521-14521 ◽  
Author(s):  
A. Buzaid ◽  
C. de Cerqueira Mathias ◽  
F. Perazzo ◽  
S. Simon ◽  
L. Fein ◽  
...  
Keyword(s):  
Latin American ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Treatment Regimens ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

14521 Background: Cetuximab (Erbitux) is a monoclonal antibody directed against EGFR that is active in combination with irinotecan in patients (pts) with mCRC, who have progressed during or after a prior irinotecan therapy. Methods: This open, single-arm phase II Latin American study investigated this combination in pts with EGFR-expressing mCRC progressing on or within 3 months of chemotherapy containing at least 6 weeks (w) of irinotecan-based therapy. The primary objective was to assess the best overall confirmed response rate (RR). Sample size calculations were based on an expected rate of 20% (±8%). Planned enrollment was 100 pts. Secondary objectives were to explore the duration of response (DOR), progression-free survival (PFS) time, the 12-week PFS rate, and overall survival time. Pts were treated with cetuximab (initial dose 400 mg/m2 then 250 mg/m2 weekly), plus irinotecan at the same dose and schedule (including dose reductions) as pre-study. Preliminary Results: Of 151 pts from 14 centers screened and in the database, 106 (70%, 3 pts missing) were EGFR-expressing and, of these, 79/106 (75%) were treated on-study. Forty (51%) were male; median age was 59 years [27–82]; 70 (89%) pts had a Karnofsky performance status = 90 and 9 (11%) pts = 80. Nineteen (24%) pts had received = 3 prior treatment regimens, 42 (53%) were previously treated with an oxaliplatin-based regimen for metastatic disease. The confirmed overall RR was 26.6% [17.3–37.7]. Median DOR was 23.9 w [17.1–30], median PFS time was 17.7 w [11.7–18.9], and the 12-week PFS rate was 58% [47–69]. Thirty-three (42%) pts were alive at data cut-off. Median survival was 9.7 months [7.9–13.1]. Treatment was well tolerated with the most common grade 3/4 adverse events including: diarrhea, 20%; neutropenia,10%; acne-like rash, 9%. No grade 3/4 infusion-related reactions were reported. Conclusions: The overall confirmed RRs observed in this heavily pretreated population fully met the expectations for the primary endpoint of this study. LABEL confirmed in a Latin American setting the activity and safety of cetuximab plus irinotecan seen in previous studies. No significant financial relationships to disclose.

Final efficacy results of NCIC CTG IND.202: A randomized phase II study of recombinant interleukin-21 (rIL21) in patients with recurrent or metastatic melanoma (MM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9032-9032 ◽  
Author(s):  
Teresa M. Petrella ◽  
Catalin Liviu Dragos Mihalcioiu ◽  
Elaine McWhirter ◽  
Karl Belanger ◽  
Kerry J. Savage ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Lesion Size ◽  
Primary Objective ◽  
Effector Memory ◽  
Prior Therapy ◽  
Randomized Phase Ii ◽  
Elevated Liver Enzymes ◽  
Biomarker Analysis

9032 Background: rIL21 is a T-cell derived cytokine with antitumor activity dependent on NK cells or CD8+ T cells through induction of central and effector memory cells. A previous phase II study demonstrated an ORR of 22.5% in previously untreated patients with MM. We conducted a multicentre randomized phase II study of MM evaluating the efficacy, toxicity, pharmacokinetics, immunogenicity, and biomarkers of rIL21 versus dacarbazine (DTIC). Methods: Eligible patients: Recurrent or MM, with either maximum tumour lesion size of < 50 mm or LDH < 2.5 x ULN and prior therapy with BRAF/MEK inhibitors allowed. Patients were treated with either rIL-21, 30 µg /kg/day dose IV daily x 5 days weeks 1, 3, 5 q 8 weeks or dacarbazine (DTIC) 1000 mg/m2 IV q 3 weeks. The primary objective was to compare progression free survival (PFS). The trial was designed to detect a hazard ratio of 1.75 with one-sided alpha of 0.1; 58 progression events were required to provide 80% power. Results: 64 patients were randomized, 32 in the rIL-21 arm and 32 in the DTIC arm. The Table summarizes key demographic and efficacy endpoints. Common rIl21 related adverse events were fatigue, rash, diarrhea, nausea, myalgia and elevated liver enzymes. At least one dose reduction/ interruption or discontinuation occurred in 32 (100%) and 27 (96.4%) of rIL21 and DTIC patients. Conclusions: Despite encouraging efficacy in prior phase I/II studies, the results suggest that rIL-21 is comparable to DTIC in this patient population. Additional biomarker analysis from this study is pending and combination studies are currently ongoing. Clinical trial information: NCT00514085. [Table: see text]

scholarly journals Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986

2012 ◽  
Vol 30 (2) ◽  
pp. 191-199 ◽  
Author(s):  
Maria De Santis ◽  
Joaquim Bellmunt ◽  
Graham Mead ◽  
J. Martijn Kerst ◽  
Michael Leahy ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Error Rates ◽  
Phase Iii ◽  
Rank Test ◽  
Treatment Groups ◽  
Randomized Phase Ii ◽  
Grade 3

Purpose This is the first randomized phase II/III trial comparing two carboplatin-based chemotherapy regimens in patients with urothelial cancer who are ineligible (“unfit”) for cisplatin chemotherapy. Patients and Methods The primary objective of the phase III part of this study was to compare the overall survival (OS) of chemotherapy-naive patients with measurable disease and an impaired renal function (glomerular filtration rate < 60 but > 30 mL/min) and/or performance score of 2 who were randomly assigned to receive either gemcitabine/carboplatin (GC) or methotrexate/carboplatin/vinblastine (M-CAVI). To detect an increase of 50% in median survival with GC compared with M-CAVI (13.5 v 9 months) based on a two-sided log-rank test at error rates α = .05 and β = .20, 225 patients were required. Secondary end points were overall response rate (ORR), progression-free survival (PFS), toxicity, and quality of life. Results In all, 238 patients were randomly assigned by 29 institutions over a period of 7 years. The median follow-up was 4.5 years. Best ORRs were 41.2% (36.1% confirmed response) for patients receiving GC versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (P = .08). Median OS was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm (P = .64). There was no difference in PFS (P = .78) between the two arms. Severe acute toxicity (death, grade 4 thrombocytopenia with bleeding, grade 3 or 4 renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of patients receiving GC and 21.2% of patients receiving M-CAVI. Conclusion There were no significant differences in efficacy between the two treatment groups. The incidence of severe acute toxicities was higher for those receiving M-CAVI.

A multicenter phase II study of bendamustine with rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8023-8023 ◽  
Author(s):  
Michinori Ogura ◽  
Kiyoshi Ando ◽  
Nozomi Niitsu ◽  
Seok Jin Kim ◽  
Ken Ohmachi ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Salvage Regimen ◽  
Prior Therapy ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

8023 Background: Effective salvage therapies are needed in patients (pts) with relapsed/refractory DLBCL after R-CHOP. Therapy with bendamustine plus rituximab (B-R) was well tolerated and effective in the preceding phase I study in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, including DLBCL. This phase II study assessed the efficacy and safety of B-R in pts with relapsed/refractory DLBCL. Methods: Pts with histologically confirmed DLBCL (excluding transformed disease) and 1-3 prior therapies received rituximab 375 mg/m2 IV on day 1 and bendamustine 120 mg/m2 IV on days 2 and 3 of each 21-day cycle, for up to 6 cycles. Recovery of neutrophil count to ≥1,000/mm3 and platelet count to ≥75,000/mm3 were required prior to the start of each cycle; treatment delays >2 weeks resulted in discontinuation. The primary endpoint was overall response rate (ORR); secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and safety. Results: A total of 63 pts were enrolled; data from 59 pts were available. Median age was 67 (range, 36-75) years with 37 pts over 65 years. The majority of pts (64.4%) had 1 prior therapy; 57 pts (96.6%) were previously treated with rituximab-containing combination chemotherapy and 8 (13.6%) had prior auto-PBSCT. Pts received a median of 4 (range, 1-6) treatment cycles. Sixteen (27.1%) pts completed 6 treatment cycles; most common reasons for early discontinuation were disease progression (n=15) and failure to meet criteria to start the next cycle (n=13). Among 59 pts evaluable for response, ORR was 62.7% with a 37.3% CR rate. The median PFS was 200 days (95% CI, 109-410). Most common grade 3/4 adverse events (AEs) included CD4 lymphocytes decreased (66.1%), neutropenia (54.2%), and thrombocytopenia (10.2%). Four (6.8%) pts discontinued due to serious AEs (cytomegalovirus infection, infection, pneumonia, and pneumonia/respiratory failure). Conclusions: B-R demonstrated promising activity in pts with relapsed/refractory DLBCL. Toxicity was primarily hematologic and generally manageable. These results suggest that B-R is a promising salvage regimen for pts with relapsed/refractory DLBCL after R-CHOP.

A phase II trial of the effect of perindopril on hand foot syndrome (HFSR) incidence and severity in patients receiving regorafenib with refractory metastatic colorectal carcinoma (mCRC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 824-824
Author(s):  
Barbara L. Melosky ◽  
Howard John Lim ◽  
Janine Davies ◽  
Sharlene Gill ◽  
Christian K. Kollmannsberger ◽  
...  
Keyword(s):  
Phase Ii ◽  
Interim Analysis ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Capillary Endothelium ◽  
Open Label ◽  
Grade 3 ◽  
Overall Survival Benefit ◽  
Ecog Ps

824 Background: Regorafenib is an oral multi-kinase inhibitor (MKI), with a demonstrated overall survival benefit in mCRC refractory to standard therapy ( PMID 23177514). The most common grade 3 adverse event (AE) reported in this trial was HFSR, with 47% of patients (pts) experiencing HFSR of all grades, and 17% with grade 3 severity. The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. Perindopril is an Angiotensin Converting Enzyme (ACE) Inhibitor indicated for the treatment of hypertension, and may also play a role in preventing endothelial dysfunction ( PMID 17140552). We hypothesized that perindopril may prevent or reduce the severity of regorafenib-induced HFSR. Methods: In this single center Phase II, open label trial, 34 pts with refractory mCRC were planned to be treated with regorafenib (160 mg/day) and perindopril (4 mg/day) with both agents given 3 weeks on and 1 week off. An interim analysis was planned after 10 evaluable pts. The primary objective was to assess the proportion of pts with any grade HSFR toxicity. Secondary endpoint included time to development of worst (grade 3) HSFR toxicity, proportion of all grades of hypertension and all grade toxicities, and progression free survival. All toxicities were evaluated using CTCAE v4.03. Results: 12 pts were accrued over a 9 month time period, and 10 pts were considered evaluable as they completed one cycle of treatment. Pt characteristics included (6 M/ 6F, mean age 62, ECOG PS 0 (25%)/ 1 (75%). A planned interim analysis was performed after 10 evaluable pts had completed their first cycle of study treatment. 5/10 (50%) experienced Grade 3 HFSR, and based on the statistical plan it was deemed highly unlikely that perindopril would lead to reduced levels of regorafenib induced HSFR compared with regorafenib alone thus enrolment was stopped. The most frequent other grade 3 toxicities included hypertension (16.7%), and increased AST (16.7%). Conclusions: The addition of perindopril to regorafenib did not appear to reduce HSFR incidence and severity in pts with refractory mCRC. Clinical trial information: NCT02651415.

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